U.S. patent application Ser. No. 353,806, filed May 22, 1989, now U.S. Pat. No. 4,902,884, describes compounds of the formula ##STR2## and the pharmaceutically salts thereof, which are calcium channel blockers and thus possess useful vasodilating activity and may be used as antihypertensive agents. In formula I and throughout this specification, the symbols are defined as follows:
R.sup.2 is ##STR3##
Y.sup.1 is lower alkyl;
Y.sup.2 is lower alkyl;
Y.sup.3 is hydrogen, alkyl, alkenyl, ##STR4## or ##STR5##
Y.sup.4 and Y.sup.5 are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen;
Y.sup.6 and Y.sup.7 are each independently hydrogen, alkyl, cycloalkyl or arylalkyl; or Y.sup.6 and Y.sup.7 together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
Y.sup.8 is hydrogen, hydroxy, alkoxy, aryloxy, or arylalkoxy;
Y.sup.9 and are each independently hydrogen, alkyl, aryl, or heteroaryl, or Y.sup.9 and Y.sup.10 together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl, or morpholinyl;
n is 0, 1, 2, or 3; and
n' is 0, 1, 2, or 3.
Exemplary formula I compounds are the compound having the structure ##STR6## and the name [2S-[2.alpha.,3.alpha.,5.alpha.,5(R*)]]-3-(acetyloxy)-2,3-dihydro-S-methox y-2-(4-methoxyphenyl)-5-(2-pyrrolidinylmethyl)-1,5-benzothiazepin-4(5H)-one , and the compound having the structure ##STR7## and the name (2S-cis)-5-[(4,5-dihydro-1H-imidazol-2-yl)methyl)-2,3-dihydro-3-hydroxy-8- methoxy-2-(4-methoxyphenyl)-l,5-benzothiazepin-4(5H)-one, monohydrochloride.
U.S. application Ser. No. 353,806, now U.S. Pat. No. 4,902,684, also indicates that the carbon atoms in the 2 and 3-positions of the benzothiazepine nucleus of the compounds of formula I are asymmetric carbons and, therefore, such compounds exist in enantiomeric and diastereomeric forms and as racemic mixtures thereof. This application also indicates that those compounds of formula I which have the cis configuration are the most potent and are therefore preferred.
According to U.S. patent application Ser. No. 353,806, now U.S. Pat. No. 4,902,684, compound I in (+)-cis form may be prepared by reacting the known racemic benzothiazepine intermediate ##STR8## with a nonracemic acid or amino acid ##STR9## wherein Z and Z.sub.1 are different, using a conventional esterifying agent (e.g., carbodiimide) with a catalyst (e.g., 4-dimethylaminopyridine) to give a mixture of diastereomers separable by conventional techniques.
In European patent application No. 154,838, the benzothiazepine ##STR10## is prepared and the isomers separated by crystallization and chromatography and then hydrolyzed to isolate the (+) isomer compound ##STR11##
The art would benefit from a procedure by which the preferred isomeric configuration could be produced earlier in the preparation of the benzothiazepines, thus maximizing yields of the preferred enantiomer of the benzothiazepine cardiovascular agents.